| 1. |
- Adelöf, Julia, 1990, et al.
(author)
-
PA28α overexpressing female mice maintain exploratory behavior and capacity to prevent protein aggregation in hippocampus as they age.
- 2021
-
In: Aging cell. - : Wiley. - 1474-9726 .- 1474-9718. ; 4:29
-
Journal article (peer-reviewed)abstract
- With age, protein damage accumulates and increases the risk of age-related diseases. The proteasome activator PA28αβ is involved in protein damage clearance during early embryogenesis and has demonstrated protective effects against proteinopathy. We have recently discovered that adult female mice overexpressing PA28α (PA28αOE) have enhanced learning and memory, and protein extracts from their hippocampi prevent aggregation more efficiently than wild type. In this study, we investigated the effect of overexpressing PA28α on aging using C57BL/6N×BALB/c F2 hybrid mice. We found that the hippocampal anti-aggregation effect was maintained in young adult (7months) to middle-aged (15months) and old (22months) PA28αOE females. While the PA28αOE influence on learning and memory gradually decreased with aging, old PA28αOE females did not display the typical drop in explorative behavior-a behavioral hallmark of aging-but were as explorative as young mice. PA28αOE lowered PA28-dependent proteasome capacity in both heart and hippocampus, and there was no indication of lower protein damage load in PA28αOE. The life span of PA28αOE was also similar to wild type. In both wild type and PA28αOE, PA28-dependent proteasome capacity increased with aging in the heart, while 26S and 20S proteasome capacities were unchanged in the timepoints analyzed. Thus, PA28αOE females exhibit improved hippocampal ability to prevent aggregation throughout life and enhanced cognitive capabilities with different behavioral outcomes dependent on age; improved memory at early age and a youth-like exploration at old age. The cognitive effects of PA28αβ combined with its anti-aggregation molecular effect highlight the therapeutical potential of PA28αβ in combating proteinopathies.
|
|
| 2. |
- Adelöf, Julia, 1990, et al.
(author)
-
Survival-Span Method: How to Qualitatively Estimate Lifespan to Improve the Study of Aging, and not Disease, in Aging Studies
- 2021
-
In: Frontiers in Aging. - : Frontiers Media SA. - 1663-4365 .- 2673-6217. ; 2
-
Journal article (peer-reviewed)abstract
- Lifespan analyses are important for advancing our understanding of the aging process. There are two major issues in performing lifespan studies: 1) late-stage animal lifespan analysis may include animals with non-terminal, yet advanced illnesses, which can pronounce indirect processes of aging rather than the aging process per se and 2) they often involves challenging welfare considerations. Herein, we present an option to the traditional way of performing lifespan studies by using a novel method that generates high-quality data and allows for the inclusion of excluded animals, even animals removed at early signs of disease. This Survival-span method is designed to be feasibly done with simple means by any researcher and strives to improve the quality of aging studies and increase animal welfare.
|
|
| 3. |
- Hernebring, Malin, 1978, et al.
(author)
-
H2O2-induced cataract as a model of age-related cataract: Lessons learned from overexpressing the proteasome activator PA28αβ in mouse eye lens.
- 2021
-
In: Experimental eye research. - : Elsevier BV. - 1096-0007 .- 0014-4835. ; 203
-
Journal article (peer-reviewed)abstract
- Cataract, the world-leading cause of blindness, is formed when crystallin aggregates cloud the eye lens. We overexpressed PA28αβ, a proteasome activator with properties protective against aggregation and oxidative stress, and examined whether they are less prone to develop cataract arisen from aging and/or hydrogen peroxide (H2O2) treatment. Another objective of this work was to compare the H2O2-induced cataracts of mouse lenses ex vivo to cataracts formed upon aging in mice. As part of an aging study of F2 hybrid C57BL/6NxBALB/c mice, ocular lenses of mature adult (7 months), middle-aged (15 months), and old (22 months of age) PA28αOE mice and their wildtype littermates (n=22-44 lenses per group) were dissected and evaluated with regard to their cataractous state. In parallel, ocular lenses from 3 to 4 months old PA28αOE and wildtype C57BL/6N littermates were treated with 100μM H2O2 every 24h for 7 days, with progression of cataract and physical appearance monitored daily. Lenses from both studies were also subjected to analysis of oxidative protein damage (carbonylation) and protein solubility. We found that overexpression of PA28αβ had no effect on neither age-related nor H2O2-induced cataract and conclude that overexpression of PA28αβ does not protect mice from developing cataract. The inefficiency of PA28αβ against cataract could be due to its anti-aggregation activity being already excessively present in the eye lens, exerted by crystallins. Crystallins are likely also constituting the 20-25kDa proteins that were the dominant carbonyl targets in the eye lens irrespective of cataractous state. Assessment of H2O2-induced cataract in relation to age-related cataract demonstrated that high molecular weight protein carbonylation correlates to cataract both in vivo and ex vivo, while reduced protein solubility is more pronounced in age-related cataract. Furthermore, this work highlights vast dissimilarities in the physical manifestations of cataract upon aging and H2O2 ex vivo treatment. Age-related cataract initiation can take various forms, as a vague general blurriness or as a barely visible demarcated opacity, while H2O2-induced cataractogenesis seems to follow a specific scheme. In mice, this scheme begins with relatively opaque peripheral areas emerging that clear up later on as the lenses start to display a hat-like appearance. This transformation takes place synchronous to swelling of the eye lens, and is likely a result of osmotic disturbances causing a phase separation between the viscous lens cortex and the more solid fibers of the lens nucleus.
|
|
